US4728643A - Method of treating psoriasis - Google Patents

Method of treating psoriasis Download PDF

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US4728643A
US4728643A US06/667,813 US66781384A US4728643A US 4728643 A US4728643 A US 4728643A US 66781384 A US66781384 A US 66781384A US 4728643 A US4728643 A US 4728643A
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compound
vitamin
cell
disease
cultured
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Michael F. Holick
Julia McLaughlin
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General Hospital Corp
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General Hospital Corp
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Application filed by General Hospital Corp filed Critical General Hospital Corp
Priority to US06/667,813 priority Critical patent/US4728643A/en
Assigned to GENERAL HOSPITAL CORPORATION THE reassignment GENERAL HOSPITAL CORPORATION THE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: HOLICK, MICHAEL F., MC LAUGHLIN, JULIA
Priority to EP85905703A priority patent/EP0202276B2/de
Priority to AT85905703T priority patent/ATE66780T1/de
Priority to JP60505046A priority patent/JP2664667B2/ja
Priority to DE8585905703T priority patent/DE3584013D1/de
Priority to PCT/US1985/002154 priority patent/WO1986002527A1/en
Priority to US07/136,207 priority patent/US5037816A/en
Publication of US4728643A publication Critical patent/US4728643A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins

Definitions

  • the present invention relates to a novel method of treating psoriasis, a disease of the skin.
  • the method comprises using vitamin D-related compounds.
  • Psoriasis is a disease of the epidermis and a major cause of disability and disfigurement, for between 2,000,000 and 8,000,000 persons in the United States. Of these, about 100,000 are severely affected.
  • the disease is diagnosed by the presence of scaling erythematous on the scalp and extender aspects of the arms and legs; psoriatic lesions often are accentuated on the sites of repeated trauma, such as the elbows and knees.
  • the papules or plaques of psoriasis often contain a silvery-white micaceous scale that is relatively easily removed in layers.
  • UV-A light becomes a potent photoactive agent and produces a remission of psoriatic lesions after several exposures.
  • Photochemotherapy requires specialized knowledge and lighting systems delivering precisely measured amounts of ultraviolet light.
  • the receptor-negative skin fibroblasts were obtained from a patient with a rare bone disorder called vitamin D dependent rickets, type ii, a heritable disorder caused by a defective or complete absence of a cytoplasmic or nuclear receptor for 1,25-dihydroxy vitamin D.
  • the dihydroxy metabolite of vitamin D 3 caused a dose-dependent inhibition of cell growth in receptor positive skin fibroblasts (about 40-50% reduction in cell growth was observed in cultures containing 10 -6 and 10 -8 M of hormone and 12% in cultures containing 10 -10 M of 1,25--(OH) 2 --D 3 ), and, by contrast, had absolutely no effect on the growth of receptor negative skin fibroblasts.
  • the vitamin D compounds usable in the treatment of psoriasis are those capable of stimulating or inducing the differentiation of tumor or normal cell lines which possess receptors for 1,25-dihydroxyvitamin D 3 .
  • Normal cell lines include cultured rodent and human keratinocytes.
  • Active compounds are also those capable of increasing the enzymatic activity of transglutaminase in the same cell system, or are those capable of inhibiting the cell growth in vitro of human skin fibroblasts. Details of these tests can be found below.
  • the vitamin D compounds, homologues, analogues or metabolites thereof which are useful in treating psoriasis are those which demonstrate activity in any of the in vitro tests.
  • an active compound is one which induces differential at physiologic concentration of a tumor or a normal cell line which possess receptors for 1,25-dihydroxyvitamin D 3 .
  • normal useable lines are for example human or rodent keratinocytes or fibroblasts.
  • tumor lines are HL-60 cell line, M-l cell line, breast tumor cells. A few tests will be described in further detail herein.
  • a first test is one which measures the differentiation of cultured keratinocytes.
  • the assay is essentially the one described by Hosomi, et al., "Regulation of Terminal Differentiation of Cultured Mouse Epidermal Cells by 1 ⁇ ,25-dihydroxy Vitamin D 3 ,” Endocrinology, 113: 1950 (1983) for mice, or that described by Clements et al. supra for the human system, both herein incorporated by reference.
  • epidermal cells are prepared from newborn C57BL mice by overnight treatment with trypsin at 4° C. followed by separation of the epidermis from the dermis with forceps.
  • Cells are plated at a density of 10 6 cells per 4.5 cm 2 well and grown in Eagle minimum essential medium (MEM) (supplemented with 10% fetal calf serum (FCS)). Cells can also be grown in low calcium medium, Eagle MEM, without calcium supplemented with 10% dialyzed FCS. Calcium concentration of the low calcium medium can be from about 0.01-0.5 mM, whereas a conventional MEM plus 10% FCS usually may contain 1.0-2.0 mM calcium. Cells are incubated in a humidified CO 2 incubator at 37° C. All experiments are performed on the primary cultures.
  • MEM Eagle minimum essential medium
  • FCS fetal calf serum
  • FCS contains 1,25--(OH) 2 --D 3 at 0.12 nm (Tanaka, H. et al., Biochem. J., 204: 713 (1982)). Therefore, the endogenous concentration of the vitamin in the control culture medium which contains 10% FCS is negligible.
  • Floating cells are collected from the medium. Then the cultures are washed with phosphate buffered saline (PBS) and attached cells are dissociated by treatment with 0.05% trypsin and 0.1% EDTA solution at 37° C. for 20-30 min. Cell suspensions are then divided into two portions: one for counting the numbers of squamous and basal cells and the other for counting cornified envelopes. Since basal cells are small and round, whereas squamous and enucleated cells are large and flat, they are readily distinguishable in a hemocytometer. The method of Sun and Green (Cell, 9: 511 (1976)) can be used to determine the presence of a cornified envelope.
  • PBS phosphate buffered saline
  • the cells are resuspended in 10 mM Tris-HCl (pH 7.4) containing 1% beta-mercaptoethanol and 1% sodium dodecylsultate at a density of 5:30 ⁇ 10 4 cells/ml. The mixture stands for 10 minutes at room temperature and then insoluble cells are counted in a hemocytometer under a phase contrast microscope.
  • the size of cells can be measured in photographs with a stage micrometer as a standard.
  • the density distribution of cells is measured by density gradient centrifugation in Percoll®.
  • Epidermal cells 8-11 ⁇ 10 6 /ml are suspended in PBS containing 40% Percoll, placed in a 10 ml polycarbonate tube, and centrifuged at 15,000 ⁇ g at 3° C. for 30 minutes in an angled rotor. Fractions are collected by use of density marker beads.
  • cells grown in a glass cover slip are fixed with either 10% formalin or methanol/acetic acid (3:1) and stained with hemotoxiline and eothine or rhodanile blue.
  • squamous cells increases in the vitamin D active treated cultures, first among the attached cell population and then among the sloughed off floating cells.
  • Epidermal differentiation can be quantified by counting cornified envelopes remaining after cell lysis with a solution containing 1% sodium dodecylsulfate and 1% beta-mercaptoethanol.
  • the percentage of cells with a cornified envelope increases with time of cultivation. The percentage is greatest after 10 days in culture when about 60-70% of the cells have an envelope. In contrast, the percentage of control cultures remain at 20% or less during a two week observation period.
  • the cells obtained in the presence of an active vitamin D compound for 3 days are larger and lighter than those in its absence.
  • the diameter of cells in the treated cultures is usually about 25 ⁇ 10 mm, compared with about 17 ⁇ 5 mm in a control.
  • a second test is that of inhibition of human skin fibroblasts. This test is found in Clemens et al., J. Clin. Endocr. Metab., 56: 824 (1983), herein incorporated by reference. Briefly, skin cells are isolated from surgically obtained normal human skin from mammary, face, thigh, etc. of a normal patient.
  • DMEM Dulbecco's modified Eagle's medium
  • Fibroblasts are plated at 7-10 ⁇ 10 4 cells in 35-mm Costar dishes in DMEM containing 5% NBS. After attachment of cells (6 hours), the media are aspirated and replaced with fresh medium containing ethanol alone (0.01%) or ethanol (0.01%) containing compound at 10 -10 , 10 -8 , 10 -6 , or 10 -4 M. At intervals thereafter, cells are harvested from duplicate plates by trypsinization and counted in a Coulter counter. Control and compound supplemented media are replaced at 4-day intervals. Normal foreskin fibroblasts, plated at 5 ⁇ 10 4 cells/well (DMEM; 5% NBS), can also be treated with ethanol (0.01%) alone or ethanol containing compound (10 -10 -10 -4 M). After 4 days, fresh medium containing the appropriate sterol is replaced, and cells are counted 2 days later, 6 days after plating.
  • transglutaminase in the keratinocyte culture.
  • the enzymatic test is carried out according to standard transglutaminase assays, Scott, K. F. F. et al., J. Cell. Physiol. 111:111-116 (1982). Any compound which when present at a concentration of 10 -12 M to 10 -3 M increases the enzymatic activity by 25% or more, preferably 50% or more, most preferably 100% or more is considered an active compound.
  • vitamin D compound which at in vitro concentrations of 10 -12 M to 10 -3 M is capable of cellular differentiation or inhibiting of fibroblast growth by at least 25%, preferably 50% is considered active.
  • Z 1 is F, H or X 1 ;
  • Q a is CF 3 or CH 2 X 1 ;
  • Q b is CF 3 or CH 3 ;
  • R is a double bond or an epoxy ##STR2## group; wherein X is selected from the group consisting of hydrogen and --OH.
  • the compounds of formula (I) When the compounds of formula (I) have a double bond at position C-22, they are derivatives of vitamin D 2 , whereas if the bond at that position is single, and there is a lack of C 24 alkyl, they are derivatives of vitamin D 3 . The latter are preferred.
  • water soluble derivatives of the aforementioned compounds of formula (1) obtained by solubilizing such compounds by attaching thereto glycosidic residues such as those disclosed in Holick, U.S. Pat. No. 4,410,515.
  • Alternative methods of solubilization are by conjugating compounds of formula (I) to glycosyl orthoester residues, as disclosed in copending U.S. Ser. No. 607,117 by Holick et. al., filed May 3, 1984.
  • the disclosures of the aforementioned patent and application are herein incorporated by reference and made a part hereof.
  • Z 2 is F, H or X 2
  • R is a double bond or an epoxy group
  • X 2 is selected from the group consisting of hydrogen, and OR 1 ,
  • R 1 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or R 1 is an ortoester glycoside moiety of the formula (III). ##STR4## where A represents a glucofuranosyl or glucopyranosyl ring;
  • R 2 is hydrogen, lower alkyl, aralkyl, or aryl
  • R 3 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, with the proviso that at least one of the R 1 is either a glycosidic residue or an orthoester glycoside moiety.
  • the vitamin D compounds are prepared or obtained according to the disclosures of the aforementioned references.
  • the 5,6- epoxy derivatives of vitamin D 3 are obtained as described in Jpn. Kokai Tokkyo Koho JP 58,216,178 [83,216,178], Dec. 15, 1983.
  • the fluoro derivatives are made or obtained as described in Shiina, et al., Arch. Biochem. Biophys 220:90 (1983).
  • the compounds of the invention can be administered in any appropriate pharmacological carrier for oral, parenteral, or topical administration. They can be administered by any means that effects palliating conditions of psoriasis in humans.
  • the dosage administered will be dependent upon the age, health and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment and the nature of the effect desired.
  • systemic daily dosage of active ingredient compounds will be from about 0.001 micrograms/kg to 100 micrograms/kg preferably 0.1 to 1.0 micrograms per kg of body weight. Normally, from 0.1 to 100 micrograms/kg per day, in one or more applications per day is effective to obtain the desired results.
  • Topical dosage would be 0.001 micrograms to 100 micrograms/cm 2 area of skin.
  • the compounds can be employed in dosage forms such as tablets, capsules, powder packets, or liquid solutions, suspensions or elixirs for oral administration, sterile liquid for formulations such as solutions or suspensions for parenteral use.
  • a pharmacologically inert topical carrier such as one comprising a gel, an ointment or a cream, including such carriers as water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters or mineral oils.
  • liquid petrolatum isopropylpalmitate, polyethylene glycol ethanol 95%, polyoxyethylene monolaurate 5% in water, sodium lauryl sulfate 5% in water, and the like.
  • Materials such as anti-oxidants, humectants, viscosity stabilizers and the like may be added, if necessary.
  • the compounds can also be administered by means of pumps or tapes.
  • Skin biopsies from involved and uninvolved sites were obtained from psoriatic patients and therefrom were obtained cultured fibroblasts.
  • An analysis of cultured fibroblasts from the psoriatic patients revealed that these possess high affinity low capacity receptors for 1,25--(OH 2 )--D 3 and that the Kd and density for these receptors in fibroblasts from the uninvolved areas were essentially no different from that found in cultured skin fibroblasts from normal subjects.
  • the fibroblasts from involved sites possessed receptors for 1,25-dihydroxyvitamin D 3 that have a normal affinity constant but possibly as much as 100% decrease in number of receptor sites when compared to the uninvolved fibroblasts.

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US06/667,813 1984-11-02 1984-11-02 Method of treating psoriasis Expired - Lifetime US4728643A (en)

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Application Number Priority Date Filing Date Title
US06/667,813 US4728643A (en) 1984-11-02 1984-11-02 Method of treating psoriasis
PCT/US1985/002154 WO1986002527A1 (en) 1984-11-02 1985-10-31 Method of treating psoriasis
JP60505046A JP2664667B2 (ja) 1984-11-02 1985-10-31 乾癬治療用医薬組成物
AT85905703T ATE66780T1 (de) 1984-11-02 1985-10-31 Zubereitung zur behandlung von psoriasis.
EP85905703A EP0202276B2 (de) 1984-11-02 1985-10-31 Zubereitung zur behandlung von psoriasis
DE8585905703T DE3584013D1 (de) 1984-11-02 1985-10-31 Zubereitung zur behandlung von psoriasis.
US07/136,207 US5037816A (en) 1984-11-02 1987-12-21 Method of treating psoriasis

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JP (1) JP2664667B2 (de)
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WO (1) WO1986002527A1 (de)

Cited By (31)

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WO1991005537A1 (en) * 1989-10-04 1991-05-02 Trustees Of Boston University Method of accelerating wound and ulcer healing and treating periodontal disease
US5037816A (en) * 1984-11-02 1991-08-06 The General Hospital Corporation Method of treating psoriasis
US5098899A (en) * 1989-03-06 1992-03-24 Trustees Of Boston University Method for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites
US5120722A (en) * 1984-02-08 1992-06-09 Hoffmann-La Roche Inc. Trihydroxy-cholecacliferol and trihydroxy-ergocalciferol for treating leukemia
US5185150A (en) * 1990-08-24 1993-02-09 Wisconsin Alumni Research Fdn. Cosmetic compositions containing 19-nor-vitamin D compounds
US5254538A (en) * 1989-10-04 1993-10-19 Trustees Of Boston University Method of treating periodontal disease
US5276061A (en) * 1990-08-24 1994-01-04 Wisconsin Alumni Research Foundation Cosmetic compositions containing 1α-hydroxyvitamin D homologs
US5321018A (en) * 1989-03-09 1994-06-14 Wisconsin Alumni Research Foundation Use of 1α-hydroxylated-19-nor-vitamin D compounds to treat psoriasis
US5366731A (en) * 1990-08-24 1994-11-22 Wisconsin Alumni Research Foundation Cosmetic compositions containing secosterol compounds
US5395829A (en) * 1990-10-04 1995-03-07 Trustees Of Boston University Compositions comprising vitamin D lumisterol analog precursors
US5459136A (en) * 1990-08-24 1995-10-17 Wisconsin Alumni Research Foundation Methods using vitamin D compounds for improvement of skin conditions
US5529991A (en) * 1992-06-22 1996-06-25 Lunar Corporation Oral 1α-hydroxyprevitamin D
US5549904A (en) * 1993-06-03 1996-08-27 Orthogene, Inc. Biological adhesive composition and method of promoting adhesion between tissue surfaces
US5763428A (en) * 1990-09-21 1998-06-09 Bone Care International, Inc. Methods of treating skin disorders with novel 1a-hydroxy vitamin D4 compounds and derivatives thereof
US5795882A (en) * 1992-06-22 1998-08-18 Bone Care International, Inc. Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations
US6211168B1 (en) * 1991-01-08 2001-04-03 Bone Care International, Inc Methods for preparation and use of 1α,24 (S)-dihydroxy vitamin D2
US20010002397A1 (en) * 1998-05-29 2001-05-31 Bone Care International, Inc 24-Hydroxyvitamin D, analogs and uses thereof
WO2001030751A3 (en) * 1999-10-25 2002-06-13 Strakan Ltd USES OF 1,25-DIHYDROXY-5,6-trans VITAMIN D COMPOUNDS AND DERIVATIVES THEREOF
US20020128240A1 (en) * 1996-12-30 2002-09-12 Bone Care International, Inc. Treatment of hyperproliferative diseases using active vitamin D analogues
US20030045509A1 (en) * 2000-07-18 2003-03-06 Bone Care International, Inc. Stabilized hydroxyvitamin D
US20030119795A1 (en) * 1998-03-27 2003-06-26 Oregon Health & Science University Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
US20030129194A1 (en) * 1997-02-13 2003-07-10 Bone Care International, Inc. Targeted therapeutic delivery of vitamin D compounds
US20030176403A1 (en) * 1997-08-29 2003-09-18 University Of Pittsburgh Of The Commonwealth System Of Higher Education Combination chemotherapy
US20030207810A1 (en) * 1996-12-30 2003-11-06 Bone Care International, Inc. Method of treating malignancy associated hypercalcemia using active vitamin D analogues
US20040009958A1 (en) * 1991-01-08 2004-01-15 Bone Care International, Inc. Methods for preparation and use of 1alpha,24(S)-dihydroxyvitamin D2
US20040023934A1 (en) * 1993-09-10 2004-02-05 Bone Care International, Inc. Method of treating prostatic diseases using active vitamin D analogues
US20040186082A1 (en) * 2003-03-20 2004-09-23 Hartman Raymond A. Enhanced phototherapy for the treatment of cancer and autoimmune disease
US20050065071A1 (en) * 2003-07-15 2005-03-24 National Research Council Of Canada Cyclic analogs of human parathyroid hormone for the treatment of conditions characterized by hyperproliferative skin cells
US6900191B1 (en) * 1997-02-25 2005-05-31 Oncquest, Inc. 1α-Hydroxyvitamin D5, its synthesis and use in cancer prevention
US20060003950A1 (en) * 2004-06-30 2006-01-05 Bone Care International, Inc. Method of treating prostatic diseases using a combination of vitamin D analogues and other agents
US20060003021A1 (en) * 2004-06-30 2006-01-05 Bone Care International, Inc. Method of treating breast cancer using a combination of vitamin d analogues and other agents

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DE3666587D1 (en) * 1985-08-02 1989-11-30 Leo Pharm Prod Ltd Novel vitamin d analogues
US4853378A (en) * 1986-10-20 1989-08-01 Sumitomo Chemical Company, Limited Fluorine derivatives of vitamin D3 and process for producing the same
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Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5120722A (en) * 1984-02-08 1992-06-09 Hoffmann-La Roche Inc. Trihydroxy-cholecacliferol and trihydroxy-ergocalciferol for treating leukemia
US5037816A (en) * 1984-11-02 1991-08-06 The General Hospital Corporation Method of treating psoriasis
US5098899A (en) * 1989-03-06 1992-03-24 Trustees Of Boston University Method for therapeutically treating psoriatic arthritis using vitamin D analogues and metabolites
US5321018A (en) * 1989-03-09 1994-06-14 Wisconsin Alumni Research Foundation Use of 1α-hydroxylated-19-nor-vitamin D compounds to treat psoriasis
WO1991005537A1 (en) * 1989-10-04 1991-05-02 Trustees Of Boston University Method of accelerating wound and ulcer healing and treating periodontal disease
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JP2664667B2 (ja) 1997-10-15
DE3584013D1 (de) 1991-10-10
JPS62501073A (ja) 1987-04-30
EP0202276B1 (de) 1991-09-04
EP0202276A1 (de) 1986-11-26

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